1H, 13C and 15N NMR data for indolo[2,3-b]quinolines, a novel potent anticancer drug family.

The complete NMR signal assignment of title compounds were carried out by extensive use of 1D and 2D NMR techniques (1H, 13C, COSY, HSQC and HMBC).

Bone turnover rate in postmenopausal women: bimodal distribution?

There is considerable evidence that elevated bone turnover is an independent form of low bone mineral density (BMD) risk factor of osteoporotic fractures. The aim of our study was to test whether a group of postmenopausal women could be divided into subgroups of high and low bone turnover rate using different pairs of bone turnover markers (one resorption, one formation). Cluster analysis was used to obtain high and low bone turnover subgroups within the study group. A magnitude of difference in lumbar spine BMD (expressed as Z-score) between high- and low-turnover groups was used as a criterion of division success. According to this criterion, the division obtained with a urinary type I collagen crosslinked N-telopeptide/bone alkaline phosphatase pair of markers appeared to be the most significant. This method of separation of two subgroups was highly concordant with the division based on the upper thresholds of the normal values for those markers found for the premenopausal women. It seems that the observed existence of high-and low-turnover subject clusters is not an incidental phenomenon, because the effects obtained for the whole study group were further confirmed by the consistent results of cluster analysis, performed separately for two randomly selected subgroups (A and B) from the study group. The results obtained appear to support the view that bone turnover rate in postmenopausal women is distributed in the bimodal fashion. This finding seems to justify further investigations of more elaborated models, enabling clinicians to individually classify their patients as low- or high-turnover cases with higher efficiency, as in the case of cutoff values for single markers.

Pharmacokinetics and toxicity of oral (-)-(S)-bromofosfamide in lung cancer patients.

The pharmacokinetics and toxicity of (-)-(S)-bromofosfamide ((2S)-(2-chloroethylamino)-3-(2-bromoethyl)-1,3,2-oxazaphosphorinae 2-oxide, CAS 146452-37-1, CBM-11) were determined in ten patients with non-small cell lung cancer following an oral dose of 1.38 g/m2 B.S.A. (Body Surface Area). The drug was given as a powder in gelatine capsules to fasting patients. Plasma samples were collected during the first 24 h after administration. All samples, after extraction with chloroform, were assayed by a reverse phase HPLC method using UV detection at 200 nm. Orally administered (-)-(S)-bromofosfamide showed relatively fast absorption kinetics. Peak concentration of 47 micrograms/ml was observed after 1 h. The average half-life was about 5 h. Toxicities associated with oral (-)-(S)-bromofosfamide therapy consisted of symptoms regarding the central nervous system, gastrointestinal tract and urinary tract. Neurotoxic symptoms were the most common clinically significant side effects and probably dose limiting.

Pharmacokinetics of (-)-(S)-bromofosfamide after intravenous and oral administration in mice.

(-)-(S)-Bromofosfamide ((2S)-(2-chloroethylamino)-3-(2-bromoethyl)-1,3,2-oxazaphosphorinane 2-oxide, CAS 146452-37-1, CBM-11) is a new potential anti-cancer drug, currently under investigation. Its pharmacokinetics and bioavailability were studied in female mice following intravenous and oral administration of the dose of 50 mg/kg. The compound was extracted from plasma samples using chloroform and analyzed by high-performance liquid chromatography with UV detection at 200 nm. Orally administered (-)-(S)-bromofosfamide was absorbed quickly, attaining a maximum level of 33.9 micrograms/ml at 5 min, and was eliminated with a half-life (t1/2) of about 0.9 h. The average half-life of intravenously administered (-)-(S)-bromofosfamide was about 0.7 h. The total plasma clearance (CL) and volume of distribution (Vd) were found to be 0.14 l/h and 4.92 l/kg, respectively. The absolute bioavailability of (-)-(S)-bromofosfamide after oral administration was 105%.

High-performance liquid chromatographic analysis for the determination of domperidone in human plasma.

A specific and sensitive high-performance liquid chromatographic method for the determination of domperidone in human plasma is described. Domperidone was isolated by solid-phase extraction using nitrile SPE cartridges. The drug was eluted with a mixture consisting of methanol-triethylamine-acetic acid, separated on a reversed-phase column, and measured by fluorimetric detection after post-column photoderivatization. The absolute extraction recovery from plasma samples was 83%. The limit of quantitation was established as 1 ng/ml. The relative standard deviation of the determination of plasma levels by this method over the standard curve concentration range was less than 10%, expect with the concentration of 1 ng/ml. The suitability of the method is shown for pharmacokinetic studies.

A bioequivalence study of two brands of glipizide tablets.

In this open, randomized, two way crossover, bioequivalence study, two 5 mg tablet preparations of glipizide (Glipizyd tabl. 5 mg, Tarchominskie Zaklady Farmaceutyczne POLFA S.A., and Glibenese tabl. 5 mg, Pfizer), were compared in 24 healthy male volunteers. Pharmacokinetic variables (mean maximum plasma concentration, mean time to reach maximum plasma concentration, and the mean area under the plasma concentration-time curve) were not statistically significantly different for the two formulations. It can be concluded that the two tablet preparations of glipizide are likely to be bioequivalent.

High-performance liquid chromatographic analysis for the determination of buspirone analogue--mesmar in rat plasma.

A simple and selective analytical method for the determination of buspirone analogue--mesmar in rat plasma is described. The procedure involves liquid-liquid extraction followed by reversed-phase high-performance chromatographic analysis with UV detection at 245 nm. No endogenous compounds were found to interfere. The absolute extraction recovery from plasma samples was 76%. The linearity was assessed in the range 0.12-2.44 nmol/ml. Stability of mesmar during processing (autosampler) and in plasma was checked. This method proved suitable for pharmacokinetic studies following single oral dose in rats.

Pyridinium crosslinks of collagen as a marker of bone resorption rates in children and adolescents: normal values and clinical application.

The aim of our study was to establish normal values of urinary pyridinoline (Pyr) and deoxypyridinoline (DPyr) excretion for children aged 3-18 years, examine the biological variability of the marker, and assess its clinical value for pediatric patients with growth hormone deficiency. Pyr and DPyr was measured in first void urine samples from 692 healthy subjects (340 boys, 352 girls) by high-performance liquid chromatography. At sampling, age, body height, and weight was recorded for all individuals. Short-term variability in crosslinks excretion was examined in four healthy children. The clinical value of the marker was studied in seven patients with growth hormone (GH) deficiency. In childhood, crosslinks excretion exceeded normal adult values by about fivefold and declined during puberty. In the age range of 13-18 years, gender-related differences in Pyr and DPyr levels were observed, presumably resulting from the earlier onset of puberty in girls. Urinary levels of Pyr and DPyr were highly correlated both in males and females. Pyr/DPyr ratio was significantly higher in adolescents than children, suggesting enhanced release of Pyr from extraosseous sources. In both genders, neither age nor anthropometric variables showed a linear effect on crosslinks excretion. The range of within-subject, short-term variability in urinary Pyr and DPyr was relatively high (CV: 6%-21%), indicating that single measurements of crosslinks excretion may not adequately reflect bone resorption rates in children. Pyr and DPyr levels were significantly lower in GH-deficient patients and normalized during human growth hormone (hGH) therapy. Significant correlations between growth velocity (GV) and crosslinks levels were found, but individual prediction of GV increment during hGH treatment may be inaccurate. Pyr/DPyr ratio was not related to GV. It is concluded that measurement of urinary Pyr and DPyr excretion in children may be a valuable tool to assess bone resorption rates in population-based studies. In individual patients, however, only qualitative evaluation of disease severity and response to treatment seems justified.

High-performance liquid chromatographic analysis for the determination of miconazole in human plasma using solid-phase extraction.

A high-performance liquid chromatographic method for the determination of miconazole in human plasma is described. A solid-phase extraction was performed on an octadecyl (C18) cartridge. Miconazole was eluted with methanol, separated on a reversed-phase column and was measured by ultraviolet detection at 230 nm. The absolute extraction recovery from plasma samples was 85%. The limit of detection was established as 5 ng/ml. The coefficient of variation of the determination of plasma levels by this method over the standard curve concentration range was less than 10%, except with the concentration of 10 ng/ml. The plasma levels of miconazole in twelve healthy volunteers given a 250-mg oral dose of two tablet forms were determined by this method.

[Pyridinoline and deoxypyridinoline excretion in urine of healthy children--dependence on age]. / Wydalanie pirydynoliny i dezoksypirydynoliny w moczu dzieci zdrowych--zaleznosc od wieku.

Pyridinoline (Pyr) and deoxypyridinoline (DPyr) are crosslinking compounds of bone collagen. Their urinary excretion is considered to be the first sensitive and specific marker of bone resorption in a number of metabolic bone diseases in adults. Application of crosslinks measurements to evaluate bone turnover rate in pediatric patients is so far limited because of lack of reference values. Therefore, the aim of our study was to determine urinary excretion of Pyr and DPyr in healthy children aged 3-18 yrs, and to evaluate the possible relationship between the levels of both compounds and body height, weight, BMC, and BMD. Pyr and DPyr levels were determined in first void urine samples obtained from 249 children (124 boys, 125 girls). Urine aliquots were hydrolysed, Pyr and DPyr extracted on CF1 cellulose, and analysed by HPLC with fluorimetric detection. Bone mineral content (BMC) and density (BMD) were measured with Lunar DPX-L apparatus in 205 children (104 boys, 101 girls) from the same population, aged over 5.5 yrs. In prepubertal children, a tendency towards lowering of urinary Pyr and DPyr levels with advancing age was shown. At puberty, urinary excretion of both crosslinks markedly decreased. This phenomenon was observed at various calendar age in girls as compared to boys, reflecting sex-dependent differences. Significant negative correlation (p < 0.0001) between urinary Pyr and DPyr levels and calendar age, body height and weight, BMC and BMD, were also found. The obtained results suggest that references values for Pyr and DPyr excretion in growing children should be related to calendar age, sex, and--in case of adolescents--phase of puberty.

[Evaluation of biological equivalency of Sustonit (Polfa) and Sustac by plethysmography]. / Ocena biorównowaznosci preparatów sustonit polfa z preparatami sustac przy uzyciu metody pletysmograficznej.

Bioequivalence of Sustonit tablets (2.6 and 6.5 mg) produced at WZF Polfa and Sustac tablets (2.6 and 6.5 mg) made by Krka (Yugoslavia) and WZF Polfa (Poland) was studied by means of the digital plethysmography. All the three drugs with the nitroglycerin content of 2.6 mg were found to be biologically equivalent. On the other hand, Sustonit (WZF Polfa) and Sustac (Krka) tablets with 6.5 mg nitroglycerin proved to possess better bioavailability than Sustac (6.5 mg) tablets produced previously at WZF Polfa.